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Alvimopan is a Food and Drug Administration–approved treatment to accelerate gastrointestinal recovery after abdominal surgery; however, benefits may vary across different procedures and contexts of care. The purpose of this study is to summarize the evidence regarding the effect of alvimopan on postoperative outcomes after abdominal surgery. Major databases (Medline, Embase, Biosis, Cochrane, Web of Science, and Scopus) were searched for randomized controlled trials and nonrandomized studies comparing alvimopan versus control. Risk of bias was assessed using Cochrane's risk of bias tool 2.0 (for randomized controlled trials) and Risk of Bias in Nonrandomized Studies-of Intervention tool (for nonrandomized studies). Results were appraised descriptively as heterogeneity in reporting and risk of bias hindered meta-analysis. Quality of evidence across different surgical procedures and contexts of care (ie, open versus minimally invasive surgery, traditional care versus enhanced recovery pathway) was evaluated using Grading of Recommendations Assessment, Development, and Evaluation. Nine randomized controlled trials and 35 nonrandomized studies were identified. Evidence of low to moderate certainty supports that alvimopan reduces length of stay and improves gastrointestinal recovery after open bowel resection and open radical cystectomy. Limited evidence supports alvimopan for surgeries not listed in Food and Drug Administration labels (ie, total abdominal hysterectomy and retroperitoneal lymph node dissection). Similar effects were observed in traditional and enhanced recovery pathway settings, but enhanced recovery pathway elements varied across studies. There is very low certainty of evidence supporting alvimopan for patients undergoing minimally invasive surgery. Evidence supports that alvimopan improves outcomes after open bowel resection and open radical cystectomy. Benefits for patients undergoing minimally invasive surgery and treated in contemporary enhanced recovery pathway settings remain uncertain. These findings contribute important new knowledge to inform evidence-based alvimopan prescribing. [ABSTRACT FROM AUTHOR]

The larval exsheathment inhibition assay (LEIA) of infective larvae (L 3 ) is an in vitro method used to evaluate the anthelmintic (AH) activity of tannin-containing plant extracts against different species of gastrointestinal nematodes, including Haemonchus contortus . Some conditions remain to be defined in order to standardize the LEIA, i.e. the optimal age of larvae produced from donor animals to use in the assays. Therefore, this study aimed at identifying the effect of age and age-related vitality of H. contortus infective larvae produced under tropical conditions, on the in vitro AH activity measured with the LEIA. The same acetone:water (70:30) extract from Acacia pennatula leaves was used to perform respective LEIA tests with H. contortus L 3 of different ages (1–7 weeks). Each week, the L 3 were tested against different concentrations of extract (1200, 600, 400, 200, 100, 40 μg/mL of extract) plus a PBS control. Bioassays were performed with a benzimidazole (Bz) resistant H. contortus (Paraíso) strain. In order to identify changes in L 3 vitality on different weeks (1–7), two assays testing larval motility were included only with PBS: the larval migration assay (LMA) and the larval motility observation assay (LMOA). Mean effective concentrations causing 50% and 90% exsheathment inhibition (EC 50 , EC 90 ) were obtained for every week using respective Probit analyses. On the first week, the larvae had lowest EC 50 and EC 90 (39.4 and 65.6 μg/mL) compared to older larvae (P < 0.05). The EC 50 and EC 90 for weeks 2–5 were similar (P > 0.05), while older larvae tended to show higher EC 50 and EC 90 (P < 0.05). Motility showed strong negative correlations with age of larvae (r ≥ −0.83; P < 0.05) and EC 50 (r ≥ −0.80; P < 0.05), suggesting that the lower extract efficacy could be associated with decaying vitality of larvae associated with age. More stable efficacy results were found between two to five weeks of age. [ABSTRACT FROM AUTHOR]

Aim: In this post hoc analysis of the EDGE study, we assessed the effectiveness and safety of vildagliptin versus other oral antidiabetes drugs (OADs) as add-on to first-line sulphonylurea (SU) therapy in patients who did not receive metformin in a real-life setting.Methods: The primary endpoint was odds of achieving an HbA1c reduction of >0.3% without tolerability issues. Secondary endpoint was odds of achieving HbA1c <7.0% without hypoglycaemia or weight gain. Changes in HbA1c, body weight; and safety were also assessed.Results: 2936 patients received vildagliptin and 820 received comparator OADs (any α-GI, TZD, glinide) as add-on to first-line SU therapy. Overall, the mean age, disease duration, HbA1c, and BMI at baseline were 57.1 years, 6.3 years, 8.5%, and 27.7kg/m(2), respectively. The odds ratios for achieving primary and secondary endpoints were 1.6 (95% CI: 1.36, 1.86; p<0.0001) and 1.8 (1.45, 2.21; p<0.0001), respectively, in favour of vildagliptin. The between-treatment differences (vildagliptin vs. comparator OAD) for the mean change in HbA1c and body weight were -0.2±0.04% (p<0.0001) and -0.8±0.16kg (p<0.0001), respectively. Overall, the incidence of adverse events was low (vildagliptin, 7% vs. comparator, 8.2%) in both groups. Similar results were observed in a subset of patients enrolled from India and patients who received TZDs as a comparator OAD.Conclusion: Under real-life settings, vildagliptin as add-on to SU monotherapy showed better glycaemic response without tolerability issues compared with other OADs. [ABSTRACT FROM AUTHOR]

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes. • HER2 is negative in most metastases that have a HER2 negative primary tumor. • A selective approach to HER2 ISH testing in metastases may be appropriate. • HER2 discordance in metastases may be predicted by morphologic or IHC differences. [ABSTRACT FROM AUTHOR]

Background Surgical management of emergent, life-threatening diseases is an important public health priority. The objectives of this study were to (1) describe acute care general surgery procedures performed at the largest referral hospital in Rwanda and (2) understand the geographic distribution of disease presentations and referral patterns. Methods We performed a retrospective review of prospectively collected acute care surgery cases performed at the Centre Hospitalier Universitaire de Kigali (CHUK) in Rwanda between June 1 and December 1, 2011. Using Pearson's χ 2 test and the Fisher exact test, we compared cases originating from within Kigali and transfers from other provinces. Geospatial analyses also were used to further describe transfer patterns. Results During the study period, 2,758 surgical interventions were performed, of which 25.6% (707/2,758) were general surgery operations. Of these, 45.4% (321/707) met the definition of acute care surgery. Only about one-third—32.3% (92/285)—of patients resided within Kigali, whereas about two-thirds—67.7% (193/285)—were transferred from other provinces. Most patients transferred from other provinces were younger than 18 years of age (40.4%; 78/193), and 83.0% (39/47) of patients older than 50 years of age originated from outside of Kigali. Specific operative indications and surgical procedures varied substantially between patients from Kigali and patients transferred from other provinces. Conclusion Emergency surgical conditions remain important contributors to the global burden of disease, particularly in low- and middle-income countries. Geographic variations exist in terms of operative diagnoses and procedures, which implies a need for improved access to surgical care at the district level with defined transfer mechanisms to greater-level care facilities when needed. [ABSTRACT FROM AUTHOR]

Summary Background & aims We investigated whether improving 25-hydroxyvitamin D status in young type 1A diabetic patients reduces reactivity of peripheral blood mononuclear cells against islet autoantigens and associates with beta-cell functional changes. Methods Eight patients with 25-hydroxyvitamin D deficiency (<20 ng/ml), out of 15 consecutive young type 1A diabetic subjects received 25-hydroxyvitamin D 3 to achieve and maintain levels above 50 ng/ml for up to one year. Peripheral blood mononuclear cell reactivity (Interferon-γ spots) against beta-cell autoantigens (glutamic acid decarboxylase 65-kD isoform, proinsulin and tyrosine phosphatase-like protein IA-2) and C-peptide during mixed meal were assessed before and after 25-hydroxyvitamin D 3 replenishment. Results Target 25-hydroxyvitamin D blood levels were safely reached and maintained. Peripheral blood mononuclear cell reactivity against glutamic acid decarboxylase 65-kD isoform (3.8 ± 4.0 vs. 45 ± 16) and proinsulin (3.5 ± 3.2 vs. 75 ± 51) decreased significantly ( p < 0.001 and p < 0.02) upon 25-hydroxyvitamin D 3 replenishment, which was correlated with 25-hydroxyvitamin D concentrations. C-peptide values remained stable after one year of treatment. Conclusions Safely restored and maintained 25-hydroxyvitamin D levels associated with reduced peripheral blood mononuclear cell reactivity against beta-cell autoantigens with no significant decrease of beta-cell function in this cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer is an aggressive malignancy, and emerging data suggest that postoperative infections may promote cancer progression. Systemic exposure to lipopolysaccharide (LPS), a Gram-negative bacterial antigen involved in such infections, has been shown to increase cancer cell adhesion to the hepatic sinusoids in vivo. We investigated the direct impact of LPS on the migratory ability of esophageal cancer cells via the LPS receptor toll-like receptor 4 (TLR4). Methods: Human esophageal squamous carcinoma cell lines and immortalized normal esophageal mucosa cells were tested for TLR4 surface expression by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. TLR4 signaling in response to LPS stimulation was tested in these cells by measuring p38 MAP kinase phosphorylation on Western blot. The impact of TLR4 signaling was measured by static adhesion assays in vitro and on early in vivo migration by intravital microscopy of the liver. Results: Upon LPS stimulation, phosphorylation of p38 was detected in the human esophageal cancer cells HKESC-2. Also, LPS-stimulated HKESC-2 cells showed a twofold increased adhesion to fibronectin and to hepatic sinusoidal endothelium. These effects were abolished by TLR4 inhibition using the small-molecule inhibitor eritoran. Adhesion to fibronectin and hepatic sinusoidal endothelium was also diminished by blockade of p38 phosphorylation and inhibitors of selectin-selectin ligand binding. Conclusion: LPS can increase the migratory ability of human esophageal cancer cells by increasing their adhesive properties through TLR4 signaling and selectin ligands. TLR4, p38, and selectin blockade may therefore prove to be a new therapeutic strategy for this aggressive malignancy. [Copyright &y& Elsevier]

Summary: Objective: Cartilage repair elicited by bone marrow stimulation can be enhanced by a chitosan-glycerol phosphate (GP)/blood implant, through mechanisms involving therapeutic inflammatory angiogenesis. The implant is formed by in situ coagulation, which can be accelerated by adding coagulation factors. We hypothesized that coagulation factors enhance acute subchondral angiogenesis in repairing drilled defects. Design: Full-thickness cartilage defects were created bilaterally in 12 skeletally mature rabbit knee trochlea, microdrilled, then allowed to bleed as a control (N = 6) or treated with chitosan-GP/blood implant (N = 6), or implant solidified with thrombin (IIa), tissue factor (TF) with recombinant human factor VIIa (rhFVIIa), or rhFVIIa alone (N = 4 each condition). At 3 weeks post-operative, quantitative stereology was used to obtain blood vessel length (L V), surface (S V), and volume (V V) density at systematic depths in two microdrill holes per defect. Collagen type I, type II and glycosaminoglycan (GAG) percent stain in non-mineralized repair tissue were analysed by histomorphometry. Results: All drill holes were healing, and showed a depth-dependent increase in granulation tissue blood vessel density (Lv, Sv, and Vv, P < 0.005). Residual chitosan implant locally suppressed blood vessel ingrowth into the granulation tissue, whereas holes completely cleared of chitosan amplified angiogenesis vs microdrill-only (P = 0.049), an effect enhanced by IIa. Chitosan implant suppressed strong Col-I, Col-II, and GAG accumulation that occurred spontaneously in drill-only bone defects (P < 0.005) and coagulation factors did not alter this effect. Conclusions: Subchondral angiogenesis is promoted by chitosan implant clearance. Chitosan implant treatment suppresses fibrocartilage scar tissue formation, and promotes bone remodeling, which allows more blood vessel migration and woven bone repair towards the cartilage lesion area. [Copyright &y& Elsevier]

Abstract: Background: Few large studies have documented the clinical and pathologic features of native valve endocarditis (NVE) independently from prosthetic valve endocarditis (PVE). Methods: A retrospective study of medical records of all patients undergoing operation for NVE at Mayo Clinic in Rochester, MN (1985–2004), was performed. Medical records were reviewed from 287 patients for demographics, infecting organism, and comorbidities. Microscopic slides from 310 valves were reviewed for features of infection. Results: The study cohort included 287 patients, with age ranging from 9 to 87 years (mean, 54), yielding 310 valves. Most (73%) were from men, and 84% were regurgitant. Risk factors included bicuspid aortic valve (23%), dental manipulation (20%), mitral valve prolapse (18%), diabetes mellitus (16%), and others (<5% each); in 15%, no risk factor was identified. The four most commonly identified organisms were viridans group streptococci (28%), Staphylococcus aureus (18%), enterococci (9%), and coagulase-negative staphylococci (8%). NVE was histologically active in 58% and healed in 42%, and affected left-sided valves in 94%. It was associated with embolization in 29%, acute heart failure in 29%, and annular abscess in 18%. Men accounted for a higher percentage of aortic NVE than mitral NVE (82% versus 63%, respectively; P=.001). Among 126 valves with active endocarditis, 25% had no microorganisms identified histologically. Conclusion: NVE affected men nearly three times as frequently as women. Diabetes mellitus emerged as a prevalent (and previously underrecognized) risk factor for NVE. The most common infecting organisms were streptococci and staphylococci. Microorganisms were identified histologically in the majority of active endocarditis cases. [Copyright &y& Elsevier]